Numerous treatments, both topical and systemic, are available for the primary and secondary skin infection caused by sensitive Gram +ve organisms such as Staphylococcus aureus, Streptococcus spp etc. Topical and systemic bacterial infection treatment compositions typically employ at least one active pharmaceutical ingredient (API) in combination with a base component. In the cream form, the APIs typically comprise an antibiotic/antibacterial such as Fusidic acid and the like.
In the currently available Fusidic acid creams, Fusidic acid in fine powder form is used as source API. The small particle size enhances its dermal contact by providing a large specific surface area and penetration, and provides a smooth feel on application to skin. However, a serious shortcoming of the fine size of Fusidic acid particles is that it presents an enormous surface area for contact and reaction with molecular Oxygen during manufacture, handling, and processing of the cream. This has serious implications to its chemical stability and results in rapid reduction in potency of the API (Fusidic acid) in the final cream formulation. Degradation due to oxidation is a major cause of instability of currently available Fusidic acid creams. Table 1 show that the degradation in the API samples (Fusidic acid) exposed to oxygen ranged between 7.7% and 11% for conditions ranging from room temperature to 45° C. when analysed at three months of exposure period at the above conditions.
It is known that greater the exposure time of Fusidic acid as the raw API to Oxygen, greater the limitations on stabilising Fusidic acid in a formulation. However, there is no published data on the stability of Fusidic acid over a period of time.
As an alternative to Fusidic acid, Sodium Fusidate is known to have been used to make dermaceutical medicaments for topical application. However, these are in the form of ointment rather than cream. Drawbacks of ointments over creams are well known and it's generally preferable to use creams rather than ointments for topical application.
Several aspects of Fusidic acid as an API are known:                It is thermolabile        It is available in cream formulations        It can be obtained from Sodium Fusidate by dissolving the latter in an aqueous phase and adding acid to the solution, whereby Fusidic acid precipitates. However, the Fusidic acid precipitate is difficult to process into a cream form first due to its coarse and uneven particle size and second retrieving Fusidic acid from wet cake involves drying and further handling which deteriorates the Fusidic acid due to exposure to oxygen        The stability of the API in a Fusidic acid cream is unreliable due to the thermolabile nature of Fusidic acid        
Stabilization of medicaments containing Fusidic acid against oxidation involves observing a number of stringent precautionary procedures during manufacture and storage. These include:                replacing Oxygen in pharmaceutical containers with inert gases such as Nitrogen, Carbon dioxide, Helium and the like        avoiding contact of the medicament with heavy metal ions which catalyze oxidation,        storing the API at reduced temperatures throughout its shelf life before processing        
In practice this means stricter controls during the manufacture as well as storage of such API (storing it typically at 2° C. to 8° C. in air-tight containers throughout their shelf life).
There is therefore a need to provide a process of making a Fusidic acid cream in which Fusidic acid will be of greater stability than the stability of the Fusidic acid in the conventional creams, particularly at the time of the manufacture of the cream, and which will sustain its stability at an acceptable level throughout its shelf life.
Next, let us look at the types of skin disorders and the methods of treatment available for them. Skin disorders can be broadly categorized as those arising from bacterial forms or fungi. Antifungal or antibacterial compositions are traditionally applied as lotions, creams or ointments. Furthermore in many instances, it is difficult to ascertain whether the skin condition is due to a bacterial agent or a fungus.
One approach to treating skin disorders is through elimination by trial and error. Antibacterial or antifungal compositions are applied in turn and response monitored and treatment modified. A major disadvantage of this approach is that treatment needs to be applied many times a day during the treatment period. This is greatly inconvenient and also not cost effective for a majority of human population, particularly in the under-developed nations.
There are several treatments available to treat skin disorders caused by bacteria or fungi. Typically, such compositions use steroids, antibacterial agents or antifungal agents, (or a fixed dose combination of these) and focus on these pharmaceutically active ingredients. The composition of such formulations is such as to enhance their physical/chemical/bio-release profile.
Many skin disorders caused by inflammation and bacterial attacks lead to itching and subsequent scratching, which, among other causes, can in turn lead to serious and complicated secondary infections. The conventionally available treatments do not focus on skin healing or rejuvenation; normally these two aspects are left to heal naturally.
The word healing as related to compromised skin conditions (cuts, wounds, infections, inflammations, abrasions, etc.) are not only about prevention, control, elimination of the source cause such as bacteria or fungi but also to restore the skin to its pre-infection state.
The current approaches of skin treatment can be broadly categorized into two stages, a. healing b. restoration of skin to pre-ailment state. The healing part comprises elimination, to the best possible extent, of the root cause of the disorder. This may be elimination of bacteria or fungi causing the infection through a suitable treatment of antibacterial or antifungal agents or reducing the inflammation through steroid treatment. While this treatment is under way, the ongoing compromised condition of the skin continues to be susceptible to secondary infections which can be of quite serious nature. In the case of scratched or wounded skin, it is important for blood clotting to occur quickly as it reduces chances of secondary infections. The focus of such treatments, which are administered through creams, lotions, ointments is on the action of active pharmaceutical ingredients. Cream bases or ointment bases are merely viewed as carriers to take APIs to the sites of disorder.
However, the aspect of restoring the skin back to its pre-disorder state is almost completely left to nature. Therefore one key drawback of the existing skin treatment approaches is that they run the risk of secondary infections due to slow blood clotting and wound healing process.
Furthermore, from the study of the prior art several lacking aspects of the existing prescription derma products used for topical treatment of skin disorders. This is manifested by the fact that the cream base matrix or the ointment base has been overlooked for any potential therapeutic benefits. In particular none of the available prior art suggests that:                Topical skin formulations can deliver skin healing or regeneration beyond the activity of the main APIs such that the therapeutic outcome of the main APIs is enhanced.        The addition of biologically active polymers (the so-called biopolymers) is a complex process in which the stability of the formulations could be compromised if the right biopolymer or naturally interacting formulation excipients or process parameters are not well thought through and optimized to enhance and complement therapy outcomes at the drug design stage itself.        Incorporation of a functionally bio-active excipient polymer in cream matrix while retaining the functional stability of the API in a single dose format of dermaceutical cream involves resolution of problems specific to the physical stability of cream matrix.        
A look at some of the existing patents illustrates the above points. Fusidic acid has been used in cream form. The PCT application WO 2009063493 discloses a combination therapy of a topical antibiotic and a topical steroid for the treatment of inflammatory dermatoses associated with secondary bacterial infections. In particular it relates to topical pharmaceutical compositions comprising a combination of fusidic acid and corticosteroid such as Mometasone furoate useful in treatment of infected eczema's such as secondarily infected dermatitis, including secondarily infected contact dermatitis, psoriasis, allergic contact dermatitis and atopic dermatitis with secondary bacterial infections of skin. In particular it claims to relate to topical pharmaceutical compositions comprising a combination of fusidic acid and corticosteroid such as Mometasone furoate useful in prevention of infection in cases of dermatitis, especially atopic dermatitis sufferers who are at risk of getting secondary bacterial infection.
The application claims to derive inventiveness on the assertion that the then existing prior art failed to disclose the composition comprising a combination of fusidic acid with corticosteroids especially Mometasone or Halobetasol. The inventors of WO 2009063493 apparently surprisingly found that antibiotic action of fusidic acid and the anti-inflammatory effect of corticosteroid, such as Mometasone both play important roles in reducing S. aureus and improving patient's symptoms and signs of skin inflammatory infections. The inventors of WO 2009063493 also apparently surprisingly found that antibiotic action of fusidic acid and the anti-inflammatory effect of a corticosteroid such as Halobetasol, both play important roles in prevention of secondary bacterial infections in patients with non-infected dermatoses and in treatment of infected steroid responsive dermatoses such as secondarily infected dermatoses including secondarily infected contact dermatitis, allergic contact dermatitis, atopic dermatitis, psoriasis and other corticosteroid responsive dermatoses (CRD) with secondary bacterial infections of skin.
The invention disclosed in WO 2009063493 relates to a combination therapy of a topical antibiotic and a topical steroid for the treatment of inflammatory dermatoses associated with secondary bacterial infections. In particular the present invention relates to topical pharmaceutical compositions comprising a combination of fusidic acid and corticosteroid such as Mometasone furoate useful in treatment of infected eczema's such as secondarily infected dermatitis, including secondarily infected contact dermatitis, psoriasis, allergic contact dermatitis and atopic dermatitis with secondary bacterial infections of skin. In particular the present invention also relates to topical pharmaceutical compositions comprising a combination of fusidic acid and corticosteroid such as Mometasone furoate useful in prevention of infection in cases of dermatitis, especially atopic dermatitis sufferers who are at risk of getting secondary bacterial infection
It is evident from the above example and other similar sources that the existing prior art does not teach or suggest:                Use of the cream base matrix as a functional element of the cream rather than a mere carrier for the main APIs        Use a known bio-polymer as a functional excipient along with anti bacterial agent Sodium Fusidate        Providing far superior healing effects as micro-film forming, blood clotting, supporting epidermal growth, microbial electrostatic immobilization take effect simultaneously rather than one after the other as would be the case in conventional single-drug therapy        Improve overall medicinal properties of the cream, complimenting the API used in the cream matrix        
There is therefore a need for a single-dose API topical treatment that will be provided in a cream base, which cream base provides therapeutical value complementary to that provided by the main APIs and serves the purpose over and above that of being a mere carrier or delivery mechanism.